The outbreak of the Severe Acute Respiratory Syndrome (SARS) epidemic in year 2002 motivated an international WHO-coordinated collaborative effort to discover the etiologic agent of this emerging disease. By March 2003 this effort culminated with the discovery and cloning of the SARS coronavirus (SARS CoV) (Marra et al. 2003; Rota et al. 2003) and within the same year its cellular receptor, Angiotensin-Converting Enzyme 2 (ACE2) was identified (W. Li et al. 2003). The extracellular aspect of S protein can further be divided into two functional sub-domains; 51 responsible for receptor recognition (amino acids 13-666) and S2 (amino acids 667-1195) which in response to 51 binding to ACE2, undergoes conformational rearrangements that enable viral fusion with the target-cell membrane (Du et al. 2009).
In general, in all CoVs, the Receptor Binding Domain (RBD) can be located within the first few hundred amino acid residues of 51, or further downstream (e.g., as in human coronavirus 229E. The RBD of SARS CoV was identified as a minimal 193-amino acid long sequence starting around residue N318. However, efforts to produce smaller independently-folding, functional receptor-binding peptides of 51 were unsuccessful. The co-crystallization of the RBD bound to its receptor ACE2, revealed that the actual binding interface lies within an extended excursion juxtaposed along the edge of the core of the RBD and constitutes the Receptor Binding Motif (RBM, residues S432-T486) (F. Li et al. 2005).
Several studies demonstrated anti-SARS human antibodies that target the SARS CoV RBM, reviewed in (Coughlin and Prabhakar 2012)). One such antibody is the human monoclonal antibody (mAb) 80R, which neutralizes SARS CoV in vitro and in vivo (Sui et al. 2004). The epitope of mAb 80R overlaps extensively with the binding surface recognized by ACE2, as is shown in the crystal structure of 80R:RBD and by competition studies for binding to S1 domain (Sui et al. 2004). Co-crystallization of mAb 80R with the RBD reveals that 9 of the 23 contact residues contained within the RBM coincide precisely with those that mediate ACE2 binding (Hwang et al. 2006), illustrating the prominence of the RBM as a bi-functional bioactive surface.
More recently, the MERS epidemic caused by the Middle East Respiratory Syndrome CoV (MERS, or EMC/2012), is an emerging public health hazard. The etiologic agent of MERS is also a CoV, this member is carried by bats and infects camels who directly or indirectly transmit it to humans. Thus far a few thousand individuals have been infected in the Middle East, Korea, Hong Kong. MERS, like SARS, causes severe respiratory track disease however with a markedly higher (>40%) mortality rate.
While considerable efforts are being made in attempt to produce prophylactic vaccines for SARS and more recently for MERS, there is currently no effective vaccine for any of these viruses. Hence there is a genuine need for an effective prophylactic CoVs vaccine. The present invention addresses this need.